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*
Department of Nutrition and Dietetics, King’s College London, London SE1 9NN, U.K.; Departments of
Clinical Biochemistry,
**
Medicine and
Cardiology, King’s College School of Medicine and Dentistry, London SE5 9PJ, U.K. and
Department of Clinical Biochemistry, Kingston Hospital, Kingston-upon-Thames, Surrey KT2 7QB, U.K.
3To whom correspondence should be addressed. E-mail: ross.hunter{at}kcl.ac.uk
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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KEY WORDS: • diarrhea • heart • protein synthesis • rats • insulin-like growth factor
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, Khoshoo and Bhan 1990
,
Turnburg 1981
). In rotavirus-induced diarrhea, there
are changes in small intestine mucosal architecture, with shortening of
the villi and deepening of the crypts (Davidson et al. 1977
). There is a loss of enterocytes, causing an increase in
cell turnover and establishing a relatively young population of cells
that are deficient in digestive enzymes and cause monosaccharide and
disaccharide malabsorption (Collins et al. 1990
).
Diarrhea results in an increased loss of Na+,
K+ and Cl- into the bowel
lumen, causing water loss (Kane et al. 1984
). This can
lead to dehydration and reduce the concentration of these
electrolytes in the plasma (Wakwe and Okon 1995
). Plasma
bicarbonate concentration can also be reduced, giving rise to a
metabolic acidosis (Kim et al. 1994
). These changes in
serum electrolytes and acid-base balance can have profound effects
on cardiac contractility and rhythm that are potentially fatal
(Frustaci et al. 1984
, Kane et al. 1984
,
Weldon et al. 1992
).
Malnutrition, ethanol consumption and cancer have all been shown to
affect protein metabolism in the heart, both reducing protein synthesis
and causing ultrastructural changes visible on microscopy (Drott et al. 1989
, Preedy and Peters 1990
,
Vandewoude et al. 1988
). It has been shown that diarrhea
adversely affects protein metabolism in skeletal muscle (Ansell et al. 1996
). However, its effects on protein metabolism in the
heart remain unknown. Although the effects of diarrhea on the heart
have been ascribed to electrolyte disturbances, the possibility that
changes in protein metabolism may adversely affect the heart in
diarrhea has been ignored. This study was designed to study the changes
in cardiac protein metabolism that occur in diarrhea and any
alterations in plasma hormones and biochemistry that accompany or
possibly influence this change.
Osmotic diarrhea was induced in rats with lactose as an established
model (Ansell et al. 1996
, Bueno et al. 1994
, Galvez et al. 1995
, Liuzzi et al. 1998
), and measurements were carried out in vivo using what is
arguably the most reliable method for measuring protein synthesis in
small laboratory animals, which effectively considers precursor pools
(Garlick et al. 1994
, Rennie et al. 1994
). Changes in the protein content of the heart, as well as
fractional and absolute rates of protein synthesis, were measured. To
ascertain whether there is any specific effect on the contractile
apparatus, the contents and rates of synthesis of different subcellular
protein fractions were also measured. Various biochemical variables
were measured, as were selected circulating hormones. Corticosterone
was chosen because it reflects any stress response that may occur, and
insulin-like growth factor
(IGF)-I4
was measured because it is a potent stimulator of protein synthesis.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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All animals were treated in accordance with the ethical guidelines
provided by the university at which the study was conducted. Osmotic
diarrhea was induced in male Wistar rats 4 wk of age (
60 g body;
Charles Rivers, Margate, Kent, U.K.) with lactose. Table 1
provides the composition of the diet. More detail regarding the vitamin
and mineral content of the dietary ingredients is given in Table 2
. The rats were housed in a humidified, temperature-controlled
environment on a 12-h light/dark cycle. The rats were kept in
wire-bottomed cages to minimize coprophagy, and there was no
bedding available as an additional source of energy. Although every
effort was made to ensure rats were fed the correct amount of energy,
the study design did not influence how the nutrients were metabolized.
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Group 2 rats consumed ad libitum the liquid diet containing lactose.
The treatment regimen induced diarrhea and is a widely used model
(Ansell et al. 1996
, Bueno et al. 1994
,
Galvez et al. 1995
, Liuzzi et al. 1998
).
The anal areas were wet, and the fur around the anus of these rats was
damp. The presence of diarrhea was distinctly conspicuous; the floors
of the cages were soiled and the stools were liquefied. These effects
were not seen in the control rats. The basis of the model is the
limited ability of intestinal tissue to metabolize lactose and, indeed,
some other sugars. The impaired ability of the small intestine to
digest the lactose raises intraluminal osmolarity. To compensate for
this, water traverses into the lumen of the intestine, to facilitate
equilibrium of osmolarity in the intracellular and extracellular
partitions. The increased water content in the lumen causes watery
stools. However, the physiological processes are not entirely this
simple because the lactose is subjected to bacterial fermentation,
giving rise to short-chain fatty acids, methane, hydrogen, carbon
dioxide and lactate (Holtug et al. 1992
). The
histological changes in the small bowel mucosa are similar to those
seen in young subjects with persistent diarrhea or gastroenteritis
(Bueno et al. 1994
).
Group 3 rats were subjected to control feeding and consumed identical amounts of the diet as consumed by group 2, although lactose was replaced by isocaloric glucose. The method of pair-feeding entailed measuring the volume of the liquid diet consumed by each rat in group 2 over a 24-h period. Using this figure, an identical amount of control liquid diet was consumed each day by a rat matched for body weight in group 3.
Processing of hearts.
After 1 wk of treatment, rates of protein synthesis were measured with
a flooding dose of [3H]phenylalanine (injected at a dose
of 150 mmol/L, 1 mL/100 g body intravenously) to label the
intramuscular and extracellular free amino acid pools. Ten minutes
after injection with phenylalanine, rats were killed, and tissue
samples were removed. Ideally, the specific radioactivity of the
precursor at the site of protein synthesis should be measured, i.e.,
that of aminoacyl tRNA. However, the measurement of aminoacyl tRNA is
difficult. In the flooding dose technique, the large amounts of
phenylalanine floods all endogenous free amino acid pools, such that
all free phenylalanine-specific radioactivities in the
different pools attain similar values (Garlick et al. 1980 and 1994
). Therefore, measurement of phenylalanine-specific
radioactivities in acid supernatants of tissue homogenates are
equivalent to those of aminoacyl tRNA and are sufficient for
calculating rates of protein synthesis (Davis et al. 1999
).
Processing of cardiac tissue for phenylalanine-specific
radioactivity measurements have been described previously
(Garlick et al. 1980
, Preedy et al. 1984 and 1985
). All steps, including homogenization, were carried out at
0–4°C, and all centrifugations were at 2000 x g
for 10 min, unless otherwise stated. Whole hearts were homogenized in
ice-cold water, and portions of heart homogenate containing
200–400 mg tissue were either immediately precipitated with
perchloric acid or used for protein fractionation (described later).
The acid supernatant was processed for specific radioactivity of the
free amino acid in the cardiac homogenate (Garlick et al. 1980
). The cardiac protein pellet was then subjected to alkali
digestion before protein estimation by the Biuret reaction
(Munro and Fleck 1969
). The protein was then
reprecipitated, and RNA was measured in the supernatant (Siddiq et al. 1993
). The protein pellet was then hydrolyzed, dried and
incubated with phenylalanine decarboxylase to obtain the specific
radioactivity of phenylalanine in the mixed protein fractions
(Garlick et al. 1980
).
Protein fractionation.
Cardiac homogenates from the above (containing 200 mg tissue) were
immediately transferred to 20 mL of low ionic strength buffer, pH 7.0
[10 mmol imidazole, 60 mmol KCl, 0.5 mmol EGTA, 4.0 mmol
MgCl2, 1.0 mmol sodium azide, and 1.0 mmol dithiothreitol
per L plus 0.5% (v/v) Triton X-100] (Smith and Sugden 1985
). After centrifugation, supernatants were decanted
(sarcoplasmic fraction). The protein pellet was then disrupted in a
ground glass homogenizer with 10 mL high ionic strength (100
mmol potassium dihydrogen orthophosphate, 50 mmol dipotassium hydrogen
orthophosphate, 300 mmol KCl, 1.0 mmol EDTA and 5.0 mmol ATP per L, pH
6.3). After centrifugation, supernatants containing solubilized
"myofibrillar" proteins were decanted. The remaining pellet
constituted the stromal fraction (Smith and Sugden 1985
). The protein fractions were then processed as described
earlier.
Calculation of protein synthesis rates.
Fractional rates of protein synthesis (defined as the percentage of
tissue protein renewed each day by synthesis, i.e.,
ks) was calculated with the equation (given
in %/d):
 |
where Sb and Si are the specific radioactivities of phenylalanine (dpm/nmol) in protein hydrolysates and free phenylalanine in acid supernatants of cardiac homogenates, respectively, and t is the period (in days) between injection of the isotope and immersion of the heart into an ice water mixture.
The amount of protein synthesis per unit RNA was calculated with the
equation [in mg protein/(d · mg nucleic acid)]:
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The absolute rate of protein synthesis (defined as the total
amount of protein synthesized each day, i.e., Vs)
was calculated from the protein content and fractional synthesis rate,
with the equation (in mg/d):
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Plasma biochemistry and hormones.
At the time of killing, blood samples were taken from rats and
processed by standard laboratory procedures for plasma biochemistry
(for methods, refer to Siddiq et al. 1991 and 1992
).
Methods for analyzing circulating corticosterone and IGF-I have been
described previously (Holt et al. 1996
, Miell et al. 1996
). Corticosterone was determined with a kit purchased
from ICN Biomedicals Inc. (Diagnostics Division, Eagle House, High
Wycombe, Bucks, U.K.). The level of detection was 8 ng/L; the
intra-assay coefficients of variation were 10.3, 7.1 and 4.4% at
analyte levels of 45.6, 166 and 370 ng/L, respectively, with interassay
coefficients of variation of 7.2, 6.5 and 7.1% at analyte levels of
119, 158 and 469 ng/L, respectively. IGF-I was measured by
radioimmunoassay using a polyclonal antibody raised against recombinant
human IGF-I as described previously (Thomas et al. 1992
). IGF-binding proteins were removed by
acid-ethanol extraction, followed by cryoprecipitation
(Breier et al. 1991
). Analysis of supernatants after
extraction by Western ligand blotting confirmed adequate binding
protein removal. The intra-assay and interassay coefficients of
variation of this assay were 3.2% at 720 µg/L and 7.3% at 580
µg/L, respectively. Plasma samples were diluted 1:30 with
radioimmunoassay buffer, and standards were prepared by serial dilution
of IGF-I standards from 0.2–100 µg/L.
Statistical analysis.
Data are means ± SEM, n = 4–6
per group. Although there were six rats in each group, some assays did
not accommodate all samples and only four or five values could be used.
Differences between means were assessed using least significant
differences (LSD) incorporating the pooled estimate of variance
(Snedecor and Cochran 1980
). Differences were considered
significant if P < 0.05.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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In comparison with rats that consumed the control diet ad libitum
(hereafter called the control group), rats with diarrhea had a lower
cardiac weight (-25%), protein content (-26%) and RNA content
(-32%). The RNA/protein content ratio was also lower in the rats with
diarrhea (-9%; Table 3
). These differences were accompanied by significant reductions in the
fractional rate of cardiac protein synthesis (-20%), as well as the
absolute rate of protein synthesis in the diarrhea group (-40%;
Table 4
). RNA activities were not affected, indicating that the lower rate of
protein synthesis in the diarrhea group was due to a decline in RNA
content (Table 4)
.
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). These differences were accompanied by a lower fractional rate of
myofibrillar protein synthesis (-15%; Table 6
), although differences in the sarcoplasmic and stromal protein
fractions were not significant (P < 0.1). The absolute
synthesis rates were lower in all cardiac fractions of
diarrhea-induced rats (-26% to -37%; Table 6
). Synthesis of the
myofibrillar proteins was the most sensitive to diarrhea, as shown by
the higher sarcoplasmic/myofibrillar
ks ratio in rats with diarrhea
compared with controls (Table 6)
.
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). The diarrhea group also had markedly lower plasma cholesterol and
triglyceride concentrations than the controls. Unfortunately, the blood
samples from these rats are particularly prone to hemolysis, leading to
artificially raised potassium levels, which have not been included.
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The pair-fed group showed differences similar to those described
above for the diarrhea group (Tables 2
3
4
5)
, so for brevity a comparison
between control and pair-fed groups has been omitted and instead
the differences between the diarrhea and pair-fed groups are
described.
Compared with the pair-fed group, the rats with diarrhea had a
lower heart weight (-10%), despite a higher body weight (+8%;
P = 0.06; not shown). Fractional synthesis rate in the
rats with diarrhea tended to be slower than in the pair-fed group
(-15%, P = 0.08; Table 4
), but this difference was
not reflected in the absolute rates of protein synthesis.
Analysis of the subcellular fractions showed a lower concentration of
stromal protein in the diarrhea group compared with the pair-fed
rats (13%; Table 5
), although there was no difference in stromal
protein content. There also was a lower fractional synthesis rate of
stromal protein in diarrhea-induced rats (-18%), although there
was no difference in the absolute rate of stromal protein synthesis
(Table 6)
. In the diarrhea-induced rats, the absolute synthesis
rate of the myofibrillar fraction was lower than that in the
pair-fed group (-22%, P = 0.08), and this was
reflected in the sarcoplasmic/myofibrillar
ks ratio, which was 7% greater in the
diarrhea group (Table 6)
.
Plasma bicarbonate and triglycerides were lower in rats with diarrhea compared with the pair-fed group. The plasma urea was lower in the pair-fed group than in the diarrhea group (P < 0.076).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Infectious diarrhea is a common cause of secondary lactose intolerance
(Collins et al. 1990
, Khoshoo and Bhan 1990
, Turnburg 1981
), and repeated episodes
reduce rates of growth and increase mortality and morbidity rates
(Bruckstein 1988
). Diarrhea causes a loss of
electrolytes into the bowel, resulting in dehydration and depletion of
serum electrolytes (Wakwe and Okon 1995
), and can lead
to a metabolic acidosis (Kim et al. 1994
). These changes
can have adverse effects on cardiac contractility and rhythm that can
be fatal (Frustaci et al. 1984
, Kane et al. 1984
, Weldon et al. 1992
). However, the effects
of osmotic diarrhea on protein synthesis in the heart are unknown. It
was our hypothesis that some of the cardiovascular changes were due to,
or reflect, a reduction in heart protein, particularly those pertaining
to the contractile apparatus.
Osmotic diarrhea caused a reduction in heart weight and protein content via a mechanism that involves reduced rates of protein synthesis. However, the RNA efficiency (rate of protein synthesis per unit RNA) remained unchanged. This indicates that the fall in the rate of protein synthesis was due to a decline in the amount of RNA (i.e., the rate of protein synthesis is also under "transcriptional control").
Analysis of the subcellular fractions revealed significant reductions
in total myofibrillar protein content. There also was a decrease in the
fractional synthesis rate for the myofibrillar fraction. The increase
in the sarcoplasmic/myofibrillar ks
ratio confirmed statistically that the myofibrillar protein fraction
was the most sensitive. This seems to indicate that myofibrillar
protein content and synthesis are controlled independent of other major
protein fractions in diarrhea, as was demonstrated in a similar study
by Preedy and Peters (1990
). The effect of diarrhea on
the content and synthesis of the contractile apparatus of the heart may
have implications for cardiac function. Clearly, the reduced ability to
synthesize new contractile proteins will have important consequences
for cardiovascular hemodynamics and possibly morbidity rates.
The contribution of malnutrition.
A key feature of this study was the inclusion of a pair-fed group.
The rats in the pair-fed group consumed identical amounts of the
diet as consumed by the diarrhea group, although the lactose was
replaced by isocaloric glucose to control for the anorexia in the
diarrhea group. Therefore, the diet of the pair-fed group was
deficient in energy compared with the diet of the ad libitum
consumption group. However, it is important to emphasize that in the
present study it was difficult to control for the urinary and fecal
losses of all micronutrients and macronutrients. Nevertheless,
malnutrition has been shown to affect protein metabolism in the heart,
both reducing protein synthesis and causing ultrastructural changes
visible on microscopic examination (Vandewoude et al. 1988
). It has also been shown that malnutrition due to a number
of causes, such as kwashiorkor, energy-restricted diets, anorexia
nervosa and cardiac cachexia, can reduce heart size and myocardial mass
(Heymsfeild et al. 1978
, Isner et al. 1979 and 1985
, Smythe et al. 1962
). Malnutrition has also
been shown to reduce stroke volume and cardiac output
(Heymsfeild et al. 1978
), potentially precipitating
heart failure.
In the pair-fed group, there were reductions in heart weight and
protein content (Table 3)
due to a reduction in the protein synthesis
rate similar to that seen in the diarrhea group. However, the heart
weight was significantly lower in the diarrhea group than in the
pair-fed group, and there was a reduction in the fractional
synthesis rate. This indicates that although the majority of the
changes seen in the diarrhea group were due to anorexia, there also was
an effect of the diarrhea itself.
There were differences between the diarrhea and pair-fed group in
the synthesis of the subcellular fractions. The
sarcoplasmic/myofibrillar ks ratio was
significantly greater in the diarrhea group compared with both the
control group and the pair-fed group. This indicates that the
selective reduction in the myofibrillar protein fractional synthesis
rate was greater in the diarrhea group than in the pair-fed group.
The mechanism for this is uncertain. The reason for this uncertainty
relates to the complexity of the metabolic changes in diarrhea. Other
studies have shown electrolyte changes (reduced plasma
Na+, K+ and
Cl-), with concomitant perturbations in levels
of plasma hormones, antioxidants and metabolic substrates. For example,
there is depletion of plasma antioxidants such as vitamins A and E
(Liuzzi et al. 1998
). A decrease in plasma glucose and
free amino acids, with a paradoxical increase in insulin and growth
hormone, has also been reported (Besterman et al. 1983
,
Lindblad et al. 1978
). All of these have the ability to
perturb cardiovascular function and biochemistry.
Differences in plasma analytes.
This study has the benefit of showing the changes in biochemical and
hormonal parameters so that any correlation with changes in cardiac
protein synthesis can be clearly demonstrated. The decrease in plasma
bicarbonate in the diarrhea group indicates that this model of diarrhea
induces a metabolic acidosis, which has been shown to occur in other
models of diarrhea (Kim et al. 1994
). This in itself may
perturb cardiac protein metabolism.
The decrease in plasma urea in the pair-fed group compared with the control group suggests that malnutrition induces a concomitant decrease in whole-body proteolysis. This, however, did not occur in the diarrhea group. Plasma creatinine remained the same, so any increase in urea was unlikely to be due to altered kidney function.
The fall in plasma cholesterol in both the diarrhea group and the
pair-fed group suggests that malnutrition causes a decrease in
hepatic synthesis of cholesterol. Changes in plasma cholesterol have
been shown to occur due to malnutrition in other studies and have been
shown to correlate closely with muscle protein mass (Taskinen et al. 2000
). Although there was a decrease in plasma
triglycerides in both the diarrhea group and the pair-fed group,
the further decrease in triglycerides in the diarrhea group relative to
the pair-fed group again indicates that the diarrhea had additional
effects that exceed those of malnutrition. Although malnutrition
accounts for the reduction in plasma cholesterol, a decrease in hepatic
synthesis of lipoproteins (involved in cholesterol and triglycerides)
due to diarrhea may account for the decrease in circulating
triglycerides. Decreases in plasma levels of certain hepatic enzymes,
such as those involved in cholesterol and triglyceride transport, have
been shown to occur due to protein energy malnutrition (Lamri et al. 1995
).
The lack of change in plasma corticosterone implies that the alterations in cardiac protein synthesis seen here are not part of a stress response. The decrease in plasma IGF-I is very suggestive of a role for this hormone in mediating the changes in cardiac protein synthesis in diarrhea. Plasma IGF-I did not differ significantly between the diarrhea and the pair-fed groups, indicating that the change in plasma IGF-I is due to malnutrition. There was, however, a trend for a lower IGF-I in the pair-fed group (P = 0.216) with a further significant decrease in the diarrhea group, suggesting that there may be some association between plasma IGF-I and cardiac myofibrillar protein synthesis. Further investigation is required to more closely define this relationship. Changes in circulating levels of amino acids and growth hormones such as insulin and growth hormone may also contribute to the changes in cardiac protein synthesis.
A possible mechanism for the change in plasma IGF-I is through a
mediator such as K+. Diarrhea causes loss of
electrolytes, including K+, into the bowel,
depleting serum K+ concentration (Wakwe and Okon 1995
). Plasma K+ has been shown
to correlate strongly with plasma IGF-I (Flyvbjerg et al. 1991
). Therefore, diarrhea may affect cardiac protein
metabolism through the reduction in plasma IGF-I shown in this study.
Bhutta et al. (1999
) showed that as children recover
from chronic diarrhea and start to gain weight, plasma IGF-I
concentrations rise. This suggests that increasing the plasma IGF-I may
halt the wasting that occurs in diarrhea. Unfortunately, due to
excessive hemolysis of the rat blood, potassium levels were not
obtained, so this relationship between plasma K+
and IGF-I in diarrhea could not be confirmed. However, regardless of
the mechanism, there are clear pathogenic changes in cardiac protein
metabolism and plasma biochemistry caused by diarrhea, a substantial
component of which is the reduction in food intake.
This is the first report on the effects of diarrhea on cardiac protein metabolism. Reduced contractile protein contents occur via a mechanism that involves a decrease in the fractional synthesis rate. The synthesis of the myofibrillar protein fraction was affected more than the other major protein fractions. Although many of the effects on protein synthesis are due to the anorexial element, there were further changes attributable to diarrhea, possibly due to the decrease in circulating IGF-I in rats with diarrhea.
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FOOTNOTES |
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2 Presented in abstract form at the Medical Research Society meeting held at the Royal College of Physicians, June 2000. [Hunter, R. J., Patel, V. B., Richardson, P. J. & Preedy, V. R. (2000) Reduced synthesis of cardiac protein in the rat in vivo in response to diarrhea. Clin. Sci. 99:10].
4 Abbreviations used: IGF-1, insulin-like growth factor-1; ks, fractional synthesis rate; kRNA, RNA efficiency; Sb, specific radioactivity of free phenylalanine in acid supernatants of cardiac homogenate; Si, specific radioactivity of phenylalanine (dpm/nmol) in protein hydrolysates; Vs, absolute synthesis rate.
Manuscript received August 15, 2000. Initial review completed September 20, 2000. Revision accepted January 2, 2001.
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